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RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA

PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION

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|1 |NAME OF THE CANDIDATE |JIJUMON SEBASTIAN |

| | | |

| |ADDRESS |DEPARTMENT OF CLINICAL PATHOLOGY, |

| | |ST.JOHN’S MEDICAL COLLEGE, |

| | |BANGALORE-34 |

|2 |NAME OF THE INSTITUTION |ST.JOHN’S NATIONAL ACADEMY OF |

| | |HEALTH SCIENCES |

|3 |COURSE OF STUDY & SUBJECT |Msc.MLT |

| | |HEMATOLOGY AND TRANSFUSION MEDICINE |

|4 |DATE OF ADMISSION TO COURSE |25-8-2010 |

|5 |TITLE |EVALUATION OF ISOLATED PROLONGED ACTIVATED PARTIAL THROMBOPLASTIN TIME IN A|

| | |TERTIARY CARE HOSPITAL |

6.0 BRIEF RESUME OF THE INTENTED WORK:

EVALUATION OF ISOLATED PROLONGED ACTIVATED PARTIAL THROMBOPLASTIN TIME IN A TERTIARY CARE HOSPITAL

6.1Need For Study

The activated partial thromboplastin time (aPTT) is frequently used to asses overall competency of the intrinsic pathway of coagulation. An abnormal prolongation may be caused by any of several abnormalities along this pathway or by many other variables including poor collection of sample, variables in laboratory, factor deficiency or presence of inhibitors. (1)

Although originally designed to confirm suspected hemophilia(2), it’s use have been expanded over the years to include monitoring of unfractionated heparin therapy(3), investigations of disseminated intravascular coagulation, rule out factor deficiency and inhibitors and as a pre-operative haemostatic screen (4).

This study is proposed to investigate the causes of an isolated prolonged aPTT in a tertiary care hospital in an attempt to evaluate the causes and facilitate guidelines for proper investigation and diagnosis. (1)

6.2 Review of literature

aPTT is the best single test for disorders of coagulation; it’s abnormal in 90% patients with coagulation disorders when properly performed. This is a screen for all coagulation factors that contribute to thrombin formation except factor VII & XIII. APTT may not detect mild clotting defect (25%-40%) which seldom causes significant bleeding (5).

Generally aPTT is used to:

▪ Monitor heparin therapy

▪ Screen for Hemophilia A and B

▪ Detect clotting inhibitors

aPTT test is ordered by the physician in specific clinical conditions:

▪ Active bleeding

▪ Liver diseases

▪ Malnutrition

▪ Malabsorption

▪ Conditions associated with acquired coagulopathies

aPTT is prolonged by deficiency of factors:

▪ I (Fibrinogen)

▪ II (Prothrombin)

▪ V (Labile Factor)

▪ VIII (Anti Hemophilic factor)

▪ IX (Christmas factor)

▪ X (Stuart – prower factor)

▪ XI (Plasma thromboplastin antecedent)

▪ XII (Hageman factor)

It’s also prolonged due to presence of specific inhibitors of clotting factors [Most frequent is antibody against factor VIII, which occur 15% in multi-transfused patients with severe hemophilia A; and circulating Lupus Anticoagulant (LA)] (5)

aPTT is a commonly requested screening test. In vivo, the initiation of coagulation depends on tissue factor-mediated factor VII (FVII) activation, and sustained thrombin generation requires activation of factors XI, IX, VIII, X, and V. For the interpretation of aPTT results, however, coagulation factor activation culminating in a fibrin clot can be organized into intrinsic, extrinsic, and common pathways. An isolated result showing aPTT prolongation suggests a deficiency or inhibitor of one or more of the intrinsic pathway clotting factors (prekallikrein, high molecular weight kininogen, factors XII, XI, IX, and VIII).

When evaluating an unexpected prolonged aPTT result,

▪ The first step is to rule out preanalytical causes of inaccuracy:

Anticoagulant contamination due to blood collection from a venous or arterial line flushed with heparin is a common artifact, and although most commercial reagents contain a substance capable of neutralizing approximately 2 U/ml of heparin, this capacity can be overwhelmed if blood is collected from heparin-containing catheters. Other preanalytical variables include the use of collection tubes containing a higher sodium citrate anticoagulant concentration (3.8% instead of 3.2%), hemolyzed samples interfering with photo-optical clot detection methods, and a prolonged time lapse between specimen collection and performance of aPTT (> 4 hours). An increase of the citrate: plasma ratio, which decreases the ionized calcium concentration [e.g., in samples from patients with high hematocrit (> 55%) or samples collected in underfilled collection tubes, may produce erroneously prolonged aPTT results. (6)

▪ The second step in evaluating an unexpected prolonged aPTT should be to repeat the aPTT assay, taking care to eliminate potential sources of preanalytical artifact. If the screening coagulation test continues to show prolonged times,

▪ The third step is to perform a mixing study on a 50:50 mixture of patient plasma and normal pooled plasma. Correction to within the reference interval is consistent with a deficiency of one or more factors, and no or partial correction is consistent with inhibitor activity due to an anticoagulant, a factor-specific neutralizing antibody, or a nonspecific lupus anticoagulant.

Values 6 sec greater than the control value are generally abnormal. Shortening of the aPTT has little clinical relevance. Normal aPTT times require the presence of the following coagulation factors: I, II, V, VIII, IX, X, XI, & XII. Notably, deficiencies in factors VII or XIII will not be detected with the aPTT test. Prolonged aPTT may indicate: (7)

▪ use of heparin (or contamination of the sample)

▪ antiphospholipid-antibody (especially lupus anticoagulant, which paradoxically increases propensity to thrombosis)

▪ coagulation factor deficiency (e.g. hemophilia)

To distinguish the above causes, mixing tests are performed, in which the patient's plasma is mixed (initially at a 50:50 dilution) with normal plasma. If the abnormality does not disappear, the sample is said to contain an "inhibitor" (heparin, antiphospholipid antibodies or coagulation factor specific inhibitors), while if it does correct a factor deficiency is more likely. Deficiencies of factors VIII, IX, XI and XII and rarely von Willebrand factor (if causing a low factor VIII level) may lead to a prolonged aPTT correcting on mixing studies.

The evaluation of minimally prolonged aPTT (6 sec greater than the control value) is one of the most commonly encountered problems in routine coagulation laboratories (5).

6.3 Objective of the study:

To investigate the causes of isolated prolonged aPTT (6 sec greater than the control value) by correction studies to facilitate proper investigation and diagnosis of the patient.

To formulate guideline for evaluation and diagnosis

7.0 Materials and methods

7.1 Design of study

The cases with isolated prolonged aPTT (6 sec greater than the control value) will be included in the study.

Further evaluation of prolonged aPTT will be done by correction tests using control, adsorbed and aged plasma. Factor assay and testing for specific and non specific inhibitors will be done if clinically indicated

The laboratory evaluation will be in correlation with the clinical features.

Medical record of patients will be retrieved. Patient age, sex, clinical findings like prolonged bleeding, anticoagulant therapy, and family history of bleeding disorder will be collected for correlation.

The further investigation is done by mixing studies or correction studies. Correction of the abnormality by an additive reagent indicates that the reagent contains the substances deficient in the test sample.

Reagents used for mixing study:

▪ Normal plasma

▪ Aged serum/plasma

▪ Adsorbed plasma

▪ Factor VIII / IX deficient plasma

Factors present in adsorbed plasma: V, VIII, XI, XII

Factors present in aged serum / plasma: II, VII, IX, X, XI and XII

Source of data

Blood samples received in hematology lab in St Johns Medical College Hospital with isolated prolonged APTT during Jan 2011 –Dec 2011

Inclusion criteria

▪ Gender : both male and female

▪ Age : no bar

▪ APTT :6 sec greater than the control

Exclusion criteria

▪ Prolonged PT (3s greater than control)

▪ Prolonged TT (3s greater than control)

Sample size

▪ 200 patients

8.0 References

1) Craig S. Kitchens MD: Prolonged activated partial thromboplastin time of unknown etiology: A prospective study of 100 consecutive cases referred for consultation. American Journal of Hematology, Volume 27, Issue 1, pages 38–45, January 1988

2) Proctor RR, Rapaport SI. The partial thromboplastin time with kaolin: a simple screening test for first stage clotting factor deficiencies. Am J Clin Pathol 1961; 36:212-9.

3) W J Chng, C Sum, P Kuperan: Causes of isolated prolonged activated partial thromboplastin time in an acute care general hospital . Singapore Med J 2005; 46(9): 450

4) Rapaport SIL. Preoperative hemostatic evaluation: which tests, if any? Blood 1983; 61:229-31

5) Jacques Wallach M.D: Interpretation of Diagnostic Tests. 6th edition: pg421-422

6) Douglas A. Triplett, M.D: Evaluation of the Minimally Prolonged APTT: Passovoy Factor or Lupus Anticoagulant? Journal of Pediatric Hematology/Oncology: August 1996 - Volume 18 - Issue 3 - pg 247-248

7) Laffan MA, Bradshaw AE. Investigation of homeostasis. In: Dacie JV,Lewis SM,eds. Practical Hematology. NewYork: Churchill Livingstone 1995:297-315

|09 |SIGNATURE OF CANDIDATE | |

|10 |REMARKS OF THE GUIDE | |

|11 |NAME & DESIGNATION OF | |

|11.1 |GUIDE |Dr.SITALAKSHMI S |

| | |DCP, DNB, PhD. |

| | |PROFESSSOR, DEPT.CLINICAL PATHOLOGY. |

| | |ST.JOHNS MEDICAL COLLEGE HOSPITAL. |

| | |BANGALORE. |

|11.2 |SIGNATURE OF THE GUIDE | |

|11.3 |HEAD OF DEPARTMENT |Dr.KARUNA RAMESH KUMAR |

| | |MD,DCP,PhD |

| | |PROFESSSOR AND HEAD, DEPT.CLINICAL PATHOLOGY. |

| | |ST.JOHNS MEDICAL COLLEGE HOSPITAL. |

| | |BANGALORE. |

|11.4 |REMARKS OF THE HOD | |

|11.5 |SIGNATURE OF THE HOD | |

|11.6 |SIGNATURE OF DEAN | |

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